The kidneys perform a variety of excretory, metabolic, regulatory, and endocrine functions. They control fluid and electrolyte homeostasis, excretion of metabolic waste products, and synthesis and degradation of several hormones. The kidneys also maintain a homeostatic plasma composition.
Renal failure can occur in a patient due to a variety of diseases and insults. Acute renal failure can result from direct renal tubular injury, renal ischemia, and intra-tubular obstruction. Chronic renal disease is progressive, necessitating repeated monitoring over time and appropriate modification of therapeutic interventions to compensate for progressive loss of kidney function. Renal failure results in diminished glomerular filtration and reduced secretion of metabolic waste products, water and electrolytes. To minimize the accumulation of these solutes, either dietary modification (to reduce their supply/production) or dialysis (to remove them from the blood) is necessary. When renal function has decreased to less than about 10% to 5% of normal, the kidneys lose their ability to perform their excretory functions. In the absence of renal replacement therapy (dialysis or transplantation), resultant fluid overload, electrolyte imbalances, and uremic syndrome can result in death.
In the United States, there are about 2.5 million patients with varying degrees of renal failure (serum creatinine>1.7 mg/dL). Approximately 300,000 of these patients require dialysis. Globally, there are approximately 300,000 dialysis patients in Europe, 20,000 in Canada, 11,000 in Australia and New Zealand, 170,000 in Japan, 80,000 in Latin America, 45,000 in Asian Pacific region, and 50,000 in China and India. The dialysis population is growing on an average at a rate of 8% per year. Of the patients in the U.S. and Europe, the majority of patients on dialysis and a variable proportion of pre-dialysis patients are prescribed multivitamin supplements.
Dietary restrictions are a cornerstone in the medical management of renal patients. Nutritional interventions in end-stage renal disease have two primary goals: (1) minimize or prevent the characteristic uremic symptoms, and (2) achieve and maintain optimal nutritional status. Control of dietary protein and maintaining non-protein caloric intake are the highest priorities. Typically, modifications in dietary phosphorus, fluid, potassium, and/or sodium intakes are also necessary to limit their accumulation in the blood or the development of hypertension.
Nutritional management in renal disease presents a number of challenges for clinicians, since renal disease can both directly and indirectly influence nutritional status. The direct effects result from alteration in the metabolism of specific nutrients. Compared with the nutritional requirements of normal healthy individuals, renal patients undergoing dialysis require more protein, calcium, folic acid and pyridoxine, while the consumption of vitamins A, C and phosphorus, magnesium, sodium, potassium, and fluids typically must be controlled.
Indirect effects of renal disease reflect, at least in part, alterations in the redox status of the body, since renal disease exemplifies one of several disease states in which the individual experiences chronic oxidative stress. The normal anti-oxidant defense system depends on the synergic interactions of multiple anti-oxidants for optimal protection against damaging radicals. Patients with chronic kidney disease have multiple abnormalities in their anti-oxidant profiles, including reported deficiencies in enzymic anti-oxidants, selenium, ascorbate, circulating vitamin E and carotenoids.
Further, loss of renal function affects nearly all other organ systems, including the heart, nerves, brain, blood vessels, gonadal function. Uremic symptoms of nausea, loss of taste, vomiting, anorexia, malaise, and pruritus may interfere directly with food preparation and consumption by renal patients and may aggravate losses of vitamins or trace minerals. These changes lead to malnutrition including a decrease in the uptake of vitamins and minerals (e.g., riboflavin, folate, and vitamin D).
In this patient population, dietary restrictions to limit the intake of potassium and phosphorus necessitate restricted intake of green vegetables, fruits and fruit juice. Dietary restrictions on fruits and vegetables may lead to deficiencies in vitamins that are obtained solely or primarily from dietary sources, e.g., ascorbate, alpha-tocopherol, and carotenoids (including lycopene, alpha-carotene, beta-carotene, and lutein). Dietary restrictions requested of a renal patient make dietary compliance difficult. The dietary restrictions complicate food selection, and patients often must substantially change their eating patterns. As a consequence, the patient's diet may become nutritionally inadequate, requiring selective vitamin and mineral supplementation to prevent deficiencies. A low-protein diet, for example, limits intake of zinc, iron, calcium, vitamin C, folate, and other B vitamins. Therefore, end-stage renal disease (ESRD) patients receiving maintenance dialysis are at elevated risk for developing vitamin and mineral deficiency.
Elevated vitamin A levels in renal patients have been reported even in the absence of supplements, and symptoms of clinical toxicity have been reported. Hypervitaminosis A is associated with increased serum calcium, triglycerides, and cholesterol and may heighten susceptibility to fractures. To minimize toxic levels, dietary vitamin A intake in renal patients should be at or below the RDI. Therefore, vitamin supplements prescribed for patients with chronic kidney disease need to be devoid of vitamin A.
In the United States, the major dietary source of the vitamin is milk that is fortified with either ergocholecalciferol or cholecalciferol. Natural sources of vitamin D are fatty fish, fish liver oil, and to a lesser extent, eggs. Because of dietary restrictions on dairy products, many chronic kidney disease (CKD) patients have a low dietary supply of vitamin D and are therefore dependent on endogenous synthesis of vitamin D in skin to maintain their requirement for this essential vitamin. Solar UV-B radiation (290-315 nm) initiates cutaneous synthesis of vitamin D by the photoconversion of 7-dehydrocholesterol to precholecalciferol. Then, over a period of 1-2 days at body temperature, precholecalciferol spontaneously isomerizes to cholecalciferol. UV-B radiation is a component of sunlight but is not usually a significant part of indoor lighting. Limited exposure to sunlight and dietary restrictions on dairy products may predispose CKD patients to vitamin D deficiency. Loss of cholesterol from the skin in the elderly impairs skin synthesis of this important vitamin. The proportion of ESRD patients that are more than 65 years of age continues to increase. Consequently, ESRD patients are likely to have an increased incidence of vitamin D deficiency compared to other individuals. The conversions by the kidney of vitamin D to the most biologically active form, 1,25(OH)2D3, is reduced in renal patients. As a consequence of the calcium, phosphate and vitamin D imbalance, bone disease and hyperparathyroidism are common findings in patients with advanced renal disease.
Vitamin E is present in leafy green and deep yellow vegetables, meat, the yolk of the egg, fruit, milk, and dairy products. While meat is restricted in uremic patients because of its atherogenic potential, the other food items listed above are restricted in dialysis patients because of their phosphorus and/or potassium content. Consequently, dialysis patients are often deficient in vitamin E.
In addition, ESRD patients typically undergo dialysis multiple times each week, and water soluble vitamins are lost during each dialysis procedure. In the past ten years the dialysis practice has changed considerably. As compared to a decade ago, today patients are dialyzed longer, using better vascular accesses and higher blood flows. Further, dialyzers with higher efficiency/flux and larger surface areas are used. Consequently, there has been an increase in the quantities of vitamins that are removed during dialysis.
Further, the average age of incident dialysis patients in the United States is 60 years, and 32% of all dialysis patients are over 65 years of age. The elderly often have poor nutritional intake and impaired nutrient absorption from the gastrointestinal tract and therefore require higher daily intake of vitamins to maintain adequate vitamin status. With increasing age of an incident dialysis patient, cardiovascular disease has reached epidemic proportions in this patient population. Furthermore, sicker patients are being dialyzed.
Aluminum accumulation in the brain and bones in renal patients has been suggested as a potential cause of the osteodystrophy and encephalopathy occurring in renal patients. A typical diet provides 2 to 100 mg of aluminum per day. Normally, the intestine is relatively impermeable to aluminum, and most dietary aluminum is excreted in the stool. Persons with renal insufficiency, particularly those receiving aluminum-containing medications, have substantially elevated blood aluminum concentrations because while absorption is unchanged, urinary excretion is greatly reduced. Citrate readily solubilizes aluminum, facilitating both its absorption and distribution throughout the body.
For all of these reasons and others not presented herein, malnutrition is very common co-morbid condition in the dialysis patient population. Oral multivitamin and mineral supplements present an optimal way to address dietary deficiencies such as those described above, and it has been a common practice in the United States and Europe to prescribe multivitamins for all patients with kidney failure, especially for those patients receiving maintenance dialysis.
TABLE 1Vitamins and minerals and concise descriptions of their physiological activities(Source:wikipedia)CompositionConcise Description of Physiological ActivityVitamin AAn essential human nutrient that is found as any of these forms: (a)retinol, the animal form of vitamin A, is a yellow fat-soluble,antioxidant vitamin with importance in vision and bone growth, itbelongs to the family of chemical compounds known as retinoids; (b)other retinoids, a class of chemical compounds that are relatedchemically to vitamin A; and (c) carotenoids or other substances thatenable the body to synthesize retinoids.Vitamin CA water-soluble, essential nutrient required in small amounts in order toallow a range of essential metabolic reactions in animals and plants.Chemically, ascorbic acid exists in two forms: the active reduced formis ascorbic acid, while the oxidized form is dehydroascorbic acid.Dehydroscorbic acid present in the diet can be reduced to the activeform in the body by enzymes and glutathione. Ascorbic acid is anantioxidant and protects the body against oxidative stress, as well asbeing needed as a coenzyme in some enzymatic reactions.Vitamin DA group of fat-soluble prohormones, the two major forms of which arevitamin D2 (or ergocalciferol) and vitamin D3 (or cholecalciferol). Theterm vitamin D also refers to metabolites and other analogues of thesesubstances. Vitamin D3 is produced in skin exposed to sunlight,specifically ultraviolet B radiation. Vitamin D plays an important rolein the maintenance of several organ systems. Vitamin D regulates thecalcium and phosphorus levels in the blood by promoting theirabsorption from food in the intestines, and by promoting re-absorptionof calcium in the kidneys. It promotes bone formation andmineralization and is essential in the development of an intact andstrong skeleton. It inhibits parathyroid hormone secretion from theparathyroid gland. Vitamin D affects the immune system by promotingimmunosuppression and anti-tumor activity.Vitamin EA fat-soluble vitamin and anti-oxidant that is provided in eightstereoisomeric forms. All of the forms have a chromanol ring, with ahydroxyl group which can donate a hydrogen atom to reduce freeradicals and a hydrophobic side chain which allows for penetration intobiological membranes. There is an alpha, beta, gamma and delta form ofboth the tocopherols and tocotrienols, determined by the number ofmethyl groups on the chromanol ring. Each form has its own biologicalactivity, the measure of potency or functional use in the body.Vitamin KA group of lipophilic, and hydrophobic, vitamins that are needed for theposttranslational modification of certain proteins, mostly required forblood coagulation. Chemically they are 2-methyl-1,4-naphthoquinonederivatives. Vitamin K2 (menaquinone, menatetrenone) is normallyproduced by bacteria in the intestines, and dietary deficiency isextremely rare unless the intestines are heavily damaged. Highconcentrations of these quinines crosslink proteins and adversely affectred cell viability.Thiamin/Vitamin B1As the pyrophosphate (TPP), a coenzyme for pyruvate dehydrogenase,α-ketoglutarate dehydrogenase, branched-chain alpha-keto aciddehydrogenase, and transketolase. The first two of these enzymesfunction in the metabolism of carbohydrates, while transketolasefunctions in the pentose phosphate pathway to synthesize NADPH andthe pentose sugars deoxyribose and ribose. In general, TPP functions asa cofactor for enzymes that catalyze the dehydrogenation(decarboxylation and subsequent conjugation to Coenzyme A) of alpha-keto acids. TPP is synthesized by the enzyme thiaminepyrophosphokinase, which requires free thiamine, magnesium, andadenosine triphosphate.Riboflavin/Vitamin B2An easily absorbed micronutrient with a key role in maintaining healthin animals. It is the central component of the cofactors FAD and FMN,and is therefore required by all flavoproteins. As such, vitamin B2 isrequired for a wide variety of cellular processes. Like the other Bvitamins, it plays a key role in energy metabolism, and is required forthe metabolism of fats, carbohydrates, and proteins.Niacin/Vitamin B3A water-soluble vitamin whose derivatives such as NADH, NAD,NAD+, and NADP play essential roles in energy metabolism in theliving cell and DNA repair. The designation vitamin B3 also includesthe corresponding amide nicotinamide, or niacinamide.Pantothenic Acid/VitaminA water-soluble vitamin required to sustain life. Pantothenic acid isB5needed to form coenzyme-A (CoA), and is critical in the metabolismand synthesis of carbohydrates, proteins, and fats.Vitamin B6A water-soluble vitamin that is present in the body as seven forms:pyridoxine (PN), pyridoxine 5′-phosphate (PNP), pyridoxal (PL),pyridoxal 5′-phosphate (PLP), pyridoxamine (PM), pyridoxamine 5′-phosphate (PMP), and 4-pyridoxic acid (PA). PN is the form that isgiven as vitamin B6 supplement, PLP is the metabolically active formand PA is the catabolite which is excreted in the urine. All forms exceptPA can be interconverted. PLP is a cofactor in many reactions of aminoacid metabolism. PLP also is necessary for the enzymatic reactiongoverning the release of glucose from glycogen.Biotin/Vitamin B7A water-soluble B-complex vitamin which is important in the catalysisof essential metabolic reactions to synthesize fatty acids, ingluconeogenesis, and to metabolize leucine.Folate/Vitamin B9A water-soluble vitamin which in its oxidized and reduced forms aresubstrates in a number of single-carbon-transfer reactions, and also areinvolved in the synthesis of dTMP (2′-deoxythymidine-5′-phosphate)from dUMP (2′-deoxyuridine-5′-phosphate). It helps convert vitaminB12 to one of its coenzyme forms and helps synthesize the DNArequired for all rapidly growing cells.Vitamin B12 SourceA fat-soluble, cobalt-containing vitamin typically provided ascyanocobalamin, a compound that is metabolized to a vitamin in the Bcomplex commonly known as vitamin B12 (or B12 for short). The namevitamin B12 is used in two different ways. In a broad sense it refers to agroup of cobalt-containing compounds known as cobalamins-cyanocobalamin (an artifact formed as a result of the use of cyanide inthe purification procedures), hydroxocobalamin and the two coenzymeforms of B12, methylcobalamin (MeB12) and 5-deoxyadenosylcobalamin(adenosylcobalamin-AdoB12).CholineA nutrient, essential for cardiovascular and brain function, and forcellular membrane composition and repair.CalciumAn element essential in muscle contraction, oocyte activation, bonesand tooth structure, blood clotting, nerve impulse transmission,regulating heartbeat, and fluid balance within cells.IronA necessary trace element used by all known living organisms. Iron-containing enzymes, usually containing heme prosthetic groups,participate in catalysis of oxidation reactions in biology, and intransport of a number of soluble gases.PhosphorusA component of DNA and RNA and essential element for all livingcells.IodineAn essential trace element; its only known roles in biology are asconstituents of the thyroid hormones, thyroxine (T4) andtriiodothyronine (T3). Thyroid hormones play a very basic role inbiology, acting on gene transcription to regulate the basal metabolicrate. The total deficiency of thyroid hormones can reduce basalmetabolic rate up to 50%, while in excessive production of thyroidhormones the basal metabolic rate can be increased by 100%. T4 actslargely as a precursor to T3, which is (with some minor exceptions) thebiologically active hormone.MagnesiumA mineral essential to the basic nucleic acid chemistry of life, and thusis essential to all cells of all known living organisms.ZincA mineral that is present in enzymes active in gene expression. It mayalso possess anti-oxidant properties, which protect against prematureaging of the skin and muscles of the body.SeleniumA substituent which is present in the active center of certain anti-oxidant enzymes, which likely are necessary for the function of all cells.CopperAn essential nutrient found primarily in the bloodstream, as a cofactorin various enzymes, and in copper-based pigments. Effectively absorbedthrough the skin.ManganeseAn essential trace nutrient in all forms of life. The classes of enzymesthat have manganese cofactors are very broad and include such classesas oxidoreductases, transferases, hydrolases, lyases, isomerases, ligases,lectins, and integrins. The best known manganese-containingpolypeptides may be arginase, the diphtheria toxin, and Mn-containingsuperoxide dismutase (Mn-SOD)ChromiumA trace element which in its trivalent form (Cr(III), or Cr3+) is requiredin trace amounts for sugar metabolism in humans.MolybdenumA cofactor of the enzyme xanthine oxidase which is involved in thepathways of purine degradation and formation of uric acid. In someanimals, adding a small amount of dietary molybdenum enhancesgrowth.
After considering price and availability, renal patients may initially select and use an over-the-counter multivitamin preparation, in other words, a dietary supplement nutritional product designed to meet the nutrient requirements of normal healthy individuals, rather than one that is appropriate for the individual's disease state. Over-the-counter multivitamin products such as the products described in Table 2 provide quantities of vitamins A, D, and C, magnesium, phosphorus, and possibly sodium and potassium that may greatly exceed the needs of a renal patient. Frequently, these conventional supplements do not meet the increased calcium, pyridoxine, and folic acid requirements of a renal patient. In addition, these products contain additional minerals that present toxicity risks for renal patients, such as chromium, iron, and tin. Conventional over-the-counter supplement formulations may contain lake dyes that are sources of metals such as aluminum that are toxic when provided to renal patients.
TABLE 2Recommended Daily Intake of vitamins and minerals in the general population andcomparison to typical “over-the-counter” multivitamin & mineral productsConcentration per Unit DoseRecommendedCentrum ® Silver ®CompositionDaily Intake (RDI)Myadec ® tablet*tablet*Vitamin A5,000IU5,000IU (as Vitamin A3,500IU (29% as beta-acetate and beta-carotene)carotene)Vitamin C60mg60mg60mgVitamin D400IU400IU (as ergocalciferol)400IUVitamin E30IU30IU45IUVitamin K80mcg25mcg (as phytonadione)10mcgThiamin/Vitamin B11.5mg1.7mg (as thiamin1.5mgmononitrate)Riboflavin/Vitamin1.7mg2mg1.7mgB2Niacin/Vitamin B320mg20mg20mgPantothenic Acid/10mg10mg10mgVitamin B5Vitamin B62mg3mg3mgBiotin/Vitamin B7300mcg30mcg30mcgFolate/Vitamin B9400mcg400mcg400mcgVitamin B12 Source6mcg6mcg25mcgCholine(Norecommendation)Calcium1,000mg162mg (as calcium200mgphosphate)Iron18mg18mg (as ferrousfumarate)Phosphorus1,000mg125mg48mgIodine148mcg150mcg (as KI)150mcgMagnesium400mg100mg (as MgO)100mgZinc15mg15mg (as zinc oxide)15mgSelenium68mcg25mcg (as sodium20mcgselenate)Copper2mg2mg (as CuO)2mgManganese2mg2.5mg2mgChromium120mcg25mcg150mcgMolybdenum75mcg25mcg (as sodium75mcgmolybdate)Other ComponentsRecommendedChloride - 36 mgPotassium - 80 mgDaily IntakePotassium - 40 mgChloride 72 mgNot EstablishedNickel - 5 mcg (as NiSO4)Boron 150 mcgTin - 10 mcg (as SnCl2)Nickel 5 mcgSilicon - 10 mcgSilicon 2 mgVanadium - 10 mcg (asVanadium 10 mcgsodium metavanadate)Lutein 250 mcgBoron - 150 mcgLycopene 300 mcgCelluloseGelatinCopovidoneCroscarmellose SodiumDextrinStearic AcidMagnesium stearatePolyethylene glycolCorn starchFD&C Red No. 40 LakeFD&C Blue No. 1 LakeFD&C Yellow No. 6 LakeGlucoseHypromelloseAcaciaResinTitanium oxideSoy*Centrum ® Silver ® is a brand name for an adult multivitamin supplement manufactured by Wyeth Consumer Healthcare. Myadec ® is a brand name for an adult multivitamin supplement manufactured by McNeil-PPC. IU is International Units; mg is milligrams; mcg is micrograms.
Nephrologists often prescribe to pre-dialysis patients the same multivitamin preparation that they prescribe to dialysis patients. The conventional vitamin preparations that are currently used in this patient population (Table 3) are similar in composition to preparations that were in use about 15 years ago.
TABLE 3Typical conventional multivitamin and mineral preparations that are prescribed toStage IV and V renal disease patientsConcentration per Unit DoseRENAX ®Nephrocaps ®5.5Dialyvitesoft-geltabletDIATX ®DIATX ®Dialyvite ®with zincCompositioncapsule(Note 2)tabletZn tablet3000 tablettabletAscorbic Acid/100mg100mg60mg60mg100mg100mgVitamin CVitamin E35IU30IUThiamine/1.5mg3mg1.5mg1.5mg1.5mg1.5mgVitamin B1Riboflavin/1.7mg2mg1.5mg1.5mg1.7mg1.7mgVitamin B2Niacin/Vitamin20mg20mg20mg20mg20mg20mgB3(Note 1)(Note 1)(Note 1)Pantothenic5mg10mg10mg10mg10mg10mgAcid/VitaminB5Pyridoxine HCl/10mg30mg50mg50mg25mg10mgVitamin B6Biotin/Vitamin150mcg300mcg300mcg300mcg300mcg300mcgB7Folate/Vitamin1mg5.5mg5mg5mg3mg1mgB9Vitamin B126mcg1mg1mg2mg1mg6mcgSourceZinc20mg25mg Zn15mg50mg(as ZnO)Selenium70mcg70mcgOther1.5mg CuComponents(as coppergluconate)Nephrocaps ® Dialysis/Stress Vitamin (a brand of vitamin marketed as a medical food by Fleming & Company Pharmaceuticals, Fenton, MO)RENAX ® 5.5 (a brand of multivitamin marketed as a medical food by Everett Laboratories, West Orange, NJ)DIATX ® and DIATX ® with zinc (brands of vitamins marketed as medical foods by PamLab LLC, Covington, LA)Dialyvite ® 3000 and Dialyvite ® with Zinc (prescription products marketed as a medical food by Hillestad Pharmaceuticals, Dialyvite Division, Woodruff, WI)
However, research over the last decade has made it apparent that dialysis patients require vitamin and mineral supplementation that is different from that of pre-dialysis patients and individuals who do not have renal disease. For example, elevated vitamin A levels in renal patients have been reported even in the absence of supplements, and symptoms of clinical toxicity have been reported. Hypervitaminosis A is associated with increased serum calcium, triglycerides, and cholesterol and may heighten susceptibility to fractures. Conventional vitamin and mineral supplements either include large doses of Vitamin A (Table 2) or do not provide carotenoid substitutes for Vitamin A. Hyperhomocysteinemia is universally present in dialysis patients. Hyperhomocysteinemia has been associated with increased risk of vascular disease including coronary, peripheral and cerebrovascular disease. Folic acid (Vitamin B9) in a dose of 1 mg/day may not be sufficient, but higher daily doses of folic acid can lower plasma homocysteine levels in up to 30% of renal patients. Conventional vitamin and mineral supplements may provide folate at the indicated doses but only as part of a formulation that is inappropriate for renal patients (Tables 2 and 3). Higher efficiency of dialysis leads to increased removal of ascorbic acid (vitamin C). Conventional vitamin and mineral supplements frequently provide inadequate doses of vitamin C (Tables 2 and 3). Likewise, Vitamin D deficiency is common in dialysis patients, and its correction is important to prevent renal bone disease. Conventional vitamin and mineral supplements either lack Vitamin D (Table 3) or provide it as part of a formulation that is inappropriate for renal patients (Table 2). Vitamin E deficiency is not uncommon in dialysis patients, and vitamin E supplementation is advisable to prevent atherosclerotic vascular disease. Conventional vitamin and mineral supplements either lack Vitamin E (Table 3) or provide it as part of a formulation that is inappropriate for renal patients (Table 2). Vitamin K is important for bone health. Dialysis patients are at risk for vitamin K deficiency due to under-nutrition and frequent antibiotic exposure. Therefore, small doses of vitamin K are indicated in dialysis patients as part of their multivitamin formulation. Conventional vitamin and mineral supplements either lack Vitamin K (Table 3) or provide it as part of a formulation that is inappropriate for renal patients (Table 2). Zinc deficiency is common in dialysis patients and may lead to impairment of immune response, loss of hair, loss of libido, impotence, loss of taste, muscle weakness etc. Conventional vitamin and mineral supplements either lack zinc (Table 3) or provide it as part of a formulation that is inappropriate for renal patients (Table 2).